JPH0818981B2 - Aqueous pump spray preparation and process for producing the same - Google Patents

Abstract

The invention relates to a nitroglycerin-containing, hydrophilic, aqueous spray of the claimed composition. The spray according to the invention is free of CFC-containing propellant gas and is distinguished by excellent storage stability and dosage accuracy.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a hydrophilic aqueous pump spray agent containing nitroglycerin and containing no propellant gas, and its production.

[0002]

Nitroglycerin, also designated as glyceryl trinitrate (GTN), is an agent for the treatment of angina attacks. Nitroglycerin is used especially in emergencies where the pharmaceutical form must be able to initiate its action quickly.

A medicinal form used for the above-mentioned special indicator,
Sublingual tablets or cleavable capsules, for example, have drawbacks.
The disadvantage is, inter alia, that after the active substance in the pharmaceutical form has been taken, it must first be liberated and dispersed before it can be dissolved and absorbed. Furthermore, if the pharmaceutical form must first be removed from the packaging and the Blister, an unnecessary loss of time can occur during the treatment of acute attacks.

In order to avoid the disadvantages of the abovementioned pharmaceutical forms, in particular GTN-containing sprays with propellant gas have been developed.
By spraying a dose containing the active substance into the mouth, a direct and rapid application of a solution of the active substance should be ensured in the largest possible area of the oral mucosa that absorbs the active substance GTN well. . For this reason, a large area must be obtained which promotes the diffusion of the active substance.

However, sprays containing propellant gases have a number of drawbacks. The lower halogenated alkane used as a propellant gas has the effect of damaging the environment. The relationship between the use of fluorochlorinated hydrocarbons and the reduction of ozone content in the upper atmosphere is well known.
Therefore, many countries regulate the use of lower halogenated alkanes as propellant gas.

Considering the range of use in which GTN-containing propellant gas sprays are used in the treatment of acute attacks of angina, the propellant gases used exhibit the disadvantage of having a drying effect. Even so, since the mouth is dry at the time of an angina attack, the drying action of the propellant gas is extremely inconvenient.

Based on the substance-specific properties of GTN, a number of nitroglycerin-containing preparations containing fat- and oil-based carrier systems have been described.

However, in this case too, the preparation must contain at least a preservative, which does not decompose the fatty acids contained in the triglyceride, causing oxidation or rancidity. is there.
However, additives of this kind in pharmaceutical agents are not undesirable in their own right, but in view of their potential to induce allergies.

Furthermore, lipophilic solvents prevent the active substance GTN, which has a desirable rate in acute attacks of angina, from being distributed to the hydrophilic mucous membranes.

In the past, the amount of lipophilic solvent used was reduced in order to improve the processability of the active substance in propellant-containing dose aerosols. However, the perfusion time (Anflutdauer) was determined by the maximum plasma concentration (C
It can be measured in the _max) and the maximum concentration at the time (t _{m ax),} but exerted a very slight influence.

P. M. Dewland and others [Herz & G
efaesse, Vol. 1, pp. 536-544 (198).
7)] is indeed 3 GTN-s with a reduced amount of lipophilic formulation, prepared with a lipophilic solution.
A high C _max value was maintained for the spray (previously mentioned in Table 1), however, t _max was not significantly different.

[0012] West German Patent No. 3246081 describes another suggestion for increasing the processability of the active substance.

In the case of the formulations described in the aforementioned West German patent specification, the proportion of propellant gas is from 60 to 95% of the formulation constituents.
Has been raised to.

In this case, the increased proportion of propellant gas is
A high concentration of active substance is achieved in a non-volatile oily solvent.

However, in addition, the medicinal substance must first diffuse from the oily active substance solution into the mucosa. However, this does not mean that the perfusion of important agents during an attack is significantly shortened (Anflutung). A high proportion of injected gas is inconvenient and should therefore be avoided due to environmental concerns raised from various points of view.

A qualitative improvement of the spray during a seizure is not possible in a propellant-containing dose-aerosol carrying a lipophilic solvent.

Furthermore, a suggestion for rapidly dispersing the active substance in the hydrophilic mucosa lies in the use of a solvent which mixes with the aqueous mucosa. In this case, the spray formulation must take into account that the solvent should sufficiently slim the active substance and be handled industrially under production conditions.

US Pat. No. 3,155,574 discloses
Propellant-containing nitroglycerin spray formulations for hydrophilic solvent-based inhalants containing the agents GTN, 1,2-propanediol and absolute ethanol are described.

Inhalants are not essential, as GTN is well inhaled into the oral mucosa in the same way that inhalation enhances biodisposability by reducing First Pass. Furthermore, it is extremely difficult for the patient to inhale when a seizure occurs. Therapiewoc
he 34, 963-970 (1984). L
Studies by aufen et al. showed that in the case of hydrophilic formulations both the appearance of the active substance in blood and the amount of inhaled substance in the blood were rapid or large compared to GTN-spray based on lipophilicity. The result is that However, the formulation composition and dosage system were not published.

EP 0310910 describes
A hydrophilic GTN-spray formulation is described which is free from fluorochlorinated hydrocarbons and which, except for the active substance, simply contains ethanol and water as solvents.

In the case of the abovementioned formulations, the lack of mucinization of GTN is disadvantageous. If the solvent evaporates (but especially the ethanol content is reduced), GT as an oily phase
N deposits in the form of droplets on the bottom of the bottle. The formulation at the same time has the disadvantage of flammability and danger of the raw material GT
The condition is that N is dissolved in ethanol and forcibly used.

West German Patent Application Publication No. 3922650
The subject of the invention is, as the subject of the invention, the agent GTN and 51-90% of one or more fatty alcohols having 2 to 4 carbon atoms and polyalkylene glycols or 1 to 2 having 2 to 8 carbon atoms. A propellant-free aerosol preparation containing nitroglycerin consisting of 10-49% of a trihydric alcohol is described. The dose system used was not mentioned.

Furthermore, in the case of the abovementioned formulations, a high content of one or more fatty alcohols having 2 to 4 carbon atoms is disadvantageous. High degree of evaporation of alcohol from commercial dose pumps and high volatility of formulation components, resulting in composition changes after long periods of non-use of the spray, which is not compatible with the pharmaceutical formulation originally present in storage containers. The composition is used when a seizure occurs. High alcohol contents are also disadvantageous from an economic point of view, since alcohol is an expensive raw material.

Polyalkylene glycols are also used in the formulations up to 49%. However, in pharmaceutical formulations, whenever possible, high molecular weight carriers are abandoned because they contain contaminants such as initiator molecules, dipolymers and tripolymers and catalyst residues. Because there is. These pollutants are of concern in terms of physiological effects.

Furthermore, the above-mentioned state-of-the-art GTN-containing spray formulations exhibit the disadvantage that they lead to non-uniform amounts and active substance concentrations per spray extrusion.

[0026]

The object of the present invention is to eliminate the drawbacks of the prior art while containing no propellant gas,
The object is to provide a hydrophilic aqueous pump spray containing nitroglycerin, which ensures a therapeutically effective blood content in the shortest possible time, even after a long pot life or repeated use.

[0027]

By the way, surprisingly, trinitrate glycerin 0.15 to 0.50% by weight, ethanol 24.50 to 24.85% by weight, propylene glycol 32.00% by weight and purified water. A spray formulation of the composition according to the invention consisting of 43.00% by weight and adjusted to a pH of 3 to 6 has a rapid perfusion (Anflutung) and a high bioprocessability for the treatment of attacks of angina. It has a very favorable pharmacokinetic behavior with which the formulation is chemically very stable. Even after repeated use over a long pot life or short time intervals, compositions corresponding to pharmaceutical preparations are guaranteed. Due to the defined alcohol content of this composition, the composition should not be stored ignoring water.

This represents one further advantage of the formulation, as it is an increased incidence of allergies.

The spray formulation is preferably 0.30% by weight nitroglycerin, 24.70% by weight ethanol, 1,2,2.
It contains 32.00% by weight of propylene glycol and 43.00% by weight of purified water and is adjusted to a pH value of 6.0.

The spray formulation is preferably 0.40% by weight nitroglycerin, 24.60% by weight ethanol, 1,2,2.
It contains 32.00% by weight of propylene glycol and 43.00% by weight of purified water and is adjusted to a pH value of 6.0.

The formulations according to the invention can be used with pump-nebulizer dosing systems on the basis of the relatively low vapor pressure determined by the composition according to the invention of the formulation ingredients. In this case, it is ensured that the known advantages of FCKW-containing nitroglycerin sprays themselves, such as a reliable dose not disappearing after the last use, irrespective of the pot life.

The embodiment of the spray according to the invention has a pH value of 6
And the following composition: Glycerol trinitrate 0.30% Ethanol 24.70% 1,2-Propylene glycol 32.00% Purified water 43.00% This preparation is qualitative and quantitative of its mixture. Based on the composition, it fulfills the qualitative requirements for pharmaceutical agents. It does not precipitate glyceryl trinitrate in the cold, even at normal winter temperatures.

The spray formulations according to the present invention can be manufactured using conventional methods and known techniques in the manufacture of pharmaceutical agents.

Therefore, the subject of the present invention is, in a manner known per se, 0.15 to 0.50% by weight of glyceryl trinitrate, 24.50 to 24.85% by weight of ethanol, 32.00 of 1,2-propylene glycol. % By weight and purified water 43.0
A process for the preparation of a spray formulation according to the invention, characterized in that 0% by weight are mixed with one another and the resulting solution is filled into a primary packaging material maintained in a corresponding dose pump equipped with a spray head. is there.

According to a preferred embodiment of the process according to the invention, 0.30% by weight nitroglycerin, 24.70 ethanol.
% By weight, 32.00% by weight of 1,2-propylene glycol and 43.00% by weight of purified water are mixed, the resulting solution is adjusted to a pH value of 6.0 and charged into a suitable primary packaging material. To be done.

According to another advantageous embodiment of the method according to the invention,
Nitroglycerin 0.40% by weight, ethanol 24.6
0% by weight, 32.00% by weight of 1,2-propylene glycol and 43.00% by weight of purified water were mixed and the resulting solution was adjusted to pH value 6.0 and packaged in a suitable primary packaging material. Be entered.

[0037]

EXAMPLES Production Example 1 a) 0.600 g of a propylene glycol-containing glyceryl trinitrate solution having a composition of 30 mg of glyceryl trinitrate and 570 mg of 1,2-propylene glycol was added with 2.50 g of ethanol and 2.63 of 1,2-propylene glycol.
0 g and 4.300 g of purified water and mixed until homogeneous. Subsequently, 0.1 n hydrochloric acid was added dropwise to adjust the pH value to 6.

The resulting solution was filtered through a PVDF-filter (pore size 0.22 μm) from Millipore. After this, the solution was filled into a brown glass bottle which was twisted on a dose pump with a spray head.

B) Alternatively, the solution may be filled into an aerosol glass bottle fitted with a dose pump having a spray head contracted.

Production Example 2 a) 30 mg of glycerine trinitrate and 57 of ethanol
Alcoholic glyceryl trinitrate solution with a composition of 0 mg.
600 g of ethanol 1.900 g (Merck),
The mixture was mixed with 3.200 g of 1,2-propylene glycol and 4.300 g of purified water, and the mixture was stirred until it became homogeneous. Subsequently, 0.1 n hydrochloric acid was added dropwise to adjust the pH value to 6.
The resulting solution was filtered through a PVDF-filter (pore size 0.22 μm) from Millipore. The solution was then filled into a brown glass bottle which was twisted on a dose pump with a spray head.

B) The solution may also be filled into an aerosol glass bottle fitted with a dose pump having a spray head which is contracted.

Production Example 3 a) Alcoholic glyceryl trinitrate having a composition of 40 mg of glyceryl trinitrate and 760 mg of anhydrous ethanol.
800 g of ethanol 1.700 g (Merck),
The mixture was mixed with 3.200 g of 1,2-propylene glycol and 4.300 g of purified water, and the mixture was stirred until it became homogeneous. Subsequently, 0.1 n hydrochloric acid was added dropwise to adjust the pH value to 6.
The resulting solution was filtered through a PVDF-filter (pore size 0.22 μm) from Millipore. The resulting solution was then filled into a brown glass bottle which was twisted and fitted with a dose pump with a spray head.

B) The solution may also be loaded into an aerosol bottle fitted with a dose pump having a spray head which is contracted.

The pump spray according to the invention has the following advantages: -It does not contain propellant gas and thus does not harm the environment-Because it contains no preservative substances, it does not cause allergies to the user-High molecular weight components Since it does not contain any of the initiator molecules or catalyst residues, there is no need to worry about its physiological effects, -high storage stability, -long working time or repeated use over and over again. Later a constant volume is guaranteed with a constant composition.

The positive properties of the pump spray according to the invention were confirmed by a pharmacokinetic study.

In a bioprocessability study, 15 subjects were randomly administered to each other spray A according to the invention, 0.10 ml anhydrous spray preparation B and the same dose of a sublingual commercial tablet after administration. 1, 2, 3, 4,
Blood content was measured at 5, 6, 7, 10, 20, 30 minutes. The commercial sublingual tablet Nitropen (registered trademark) is
It consisted of 0.3 mg of GTN and regular tablet aids. Anhydrous spray (B) is glyceryl trinitrate 0.3
The composition was 77% by weight, 89.623% by weight ethanol, and 10.0% by weight 1,2-propylene glycol. Spray (A) is the composition described by Preparation Example 2.

The bioprocessability results are summarized in Table 1: Table 1-Pharmacokinetic data AUC C _max t _max [mg / ml] [mg / ml] [min] Sublingual Tablets 23.408 3.053 5.667 Spray according to the invention (A) 24.797 2.938 3.667 Anhydrous spray (B) 22.601 3.633 4.333 In a pharmacokinetic study, a spray according to the invention. A achieved the shortest perfusion time (Anfluzeit) (shortest t _max ), while the sublingual tablet had the slowest perfusion and the longest t.
shows _max . Spray B containing no water is in between.

Results of this study Perfusion rate (Anflutg
It has been found that the eschwindigit) is surprisingly sensitive to the melting properties of the preparation for the active substance, so that it achieves a rapid relief from the pain for the patient at the time of a seizure.

Surprisingly, the formulation A according to the invention
In a functional test of formulation B with a commercial pump dose nebulizer,
It turned out to be excellent: Storage condition of the spray Loss due to evaporation during 50 days at room temperature Spray A according to the invention Comparison spray B [mg] [mg] Vertical 3.6 ± 3.7 30.6 ± 26 .1 Horizontal 12.2 ± 6.8 118.5 ± 37.6 Inverted 12.1 ± 7.5 58.9 ± 30.1 The spray A according to the present invention has a quality guarantee period of 3 years which is usual for pharmaceutical agents. Under adverse storage conditions estimated within 2
This resulted in a slight weight loss of 70 mg. Comparative Spray B, in contrast, can suffer a weight loss of 2.6 g over 3 years,
This shortens the quality assurance period of pharmaceutical agents.

With a loading of the solution / spray container of about 10 to 20 g, a sufficient stability of the medicinal agent is qualitatively and quantitatively achievable only with the solution A according to the invention.

Special requirements should be imposed on pump dose nebulizers of solutions for biological applications such as the treatment of angina attacks: for example, unlike disinfectants or the like, administration The operability of the quantity must be guaranteed even after a rest period after the last spray application. Many commercial dose pumps must be pumped several times after only one pot life. The contents of the dosing chamber were not sealed and had evaporated without any hindrance. When a metering pump that structurally seals the contents in the metering device is used, the trial operation of the pump (Ampumpen) can be eliminated.

The requirement to dispense a complete dose in the first spraying operation irrespective of the period of non-use of the spray after the last use can be achieved with the solution A according to the invention: Despite the dosing chamber seal, evaporation losses can occur depending on the vapor pressure of the solution to be dispensed and the swelling or de-swelling action on the pump part depending on the surface tension of the solution. This is especially true of conventional spray formulations.

A comparative study between the spray formulation A according to the invention and a conventional spray formulation shows that with the spray formulation A according to the invention, even after 36 days of non-use,
It proved that the required dosage range was achieved with a single spray extrusion. Spray extrusion was calculated with 12 pump sprays, 81.8% ± 6.8% of average spray amount
Is.

Claims (6)

[Claims] 1. A dispensing for the hydrophilic aqueous pump spray containing Nitoroguriseri down, dispensing nitroglycerin 0.15 to 0.50 wt%, ethanol 24.50
~ 24.85% by weight, 1,2-propylene glycol 3
Characterized in that it contains 2.00% by weight and 43.00% by weight of purified water and is adjusted to a pH value of 3-6.
Aqueous pump spray formulation. 2. The preparation contains 0.30% by weight of nitroglycerin, 24.70% by weight of ethanol, 32.00% by weight of 1,2-propylene glycol and 43.00% by weight of purified water and has a pH value. The aqueous pump spray formulation according to claim 1, which is adjusted to 6.0. 3. The preparation contains 0.40% by weight of nitroglycerin, 24.60% by weight of ethanol, 32.00% by weight of 1,2-propylene glycol and 43.00% by weight of purified water and has a pH value of 6. The aqueous pump spray formulation according to claim 1, which is adjusted to 0. 4. A method for producing a hydrophilic formulations for aqueous pump spray containing Nitoroguriseri emissions according to claim 1, nitroglycerin 0.15 in a manner known per se
~ 0.50% by weight, ethanol 24.50-24.85
%, 1,2-propylene glycol 32.00% by weight and purified water 43.00% by weight, and the resulting solution is adjusted to pH 3-6 and introduced into a suitable primary packaging material. wherein, preparation for aqueous pump spray dispensing of the hydrophilic containing Nitorogurise <br/> re down according to claim 1. 5. Nitroglycerin 0.1% by a method known per se.
40% by weight, ethanol 24.70% by weight, 1,2-propylene glycol 32.00% by weight and purified water 4
3.00% by weight was mixed and the resulting solution was adjusted to pH value 6.0.
5. Incorporating into a suitable primary packaging material according to claim 4,
The described method. 6. Nitroglycerin 0.1% by a method known per se.
40% by weight, ethanol 24.60% by weight, 1,2-propylene glycol 32.00% by weight and purified water 4
3.00% by weight was mixed and the resulting solution was adjusted to pH value 6.0.
5. The method according to claim 4, wherein the method is adjusted to 1 and introduced into a suitable primary packaging material.